Down syndrome (DS) is the most common cause of genetically determined intellectual disability in the United States, affecting approximately 1 in 700 live births and an estimated 350,000 Americans. A close clinical pathologic association has been established between DS and Alzheimer?s disease (AD), which has become a paramount concern since improved medical care has increased the life expectancy of those with DS to close to 60 years of age. Individuals with DS exhibit AD neuropathological hallmarks including amyloid plaques and neurofibrillary tangles as early as 30 years of age. We were the first to demonstrate that AD biomarkers in neuron-derived exosomes in blood were elevated early in life of those with DS, and that phosphorylated Tau (p- Tau) was increased, and amyloid decreased following a diagnosis of dementia in DS-AD. Increased Tauopathy is seen cortico-cortical projection neurons, which form a substrate for memory connectomes in both DS and AD including the neocortical dorsal memory network (DMN) consisting of prefrontal, precuneus and posterior cingulate cortex. These structures form a key cortical network for working/declarative memory, which is dysfunctional in AD and DS. There is virtually no information identifying the molecular and cellular events resulting from trisomy overexpression of HSA21 in the DMN that underlie differences in tau aggregation within selectively vulnerable cortico-cortical neurons in subjects with DS with dementia compared to those without dementia. In the current proposal we will focus on validation of exosomal biomarkers for conversion to dementia in DS-AD and idiopathic AD, as well as examine Tau pathology in exosomes, CSF, and post mortem brain tissue. The Overall Hypothesis for this application is: Tau plays an early role in DS-AD and exosomal Tau properties can predict onset of dementia. To address this hypothesis, we are utilizing blood samples and brain tissue from cognitively well characterized individuals with DS, DS-AD, non-cognitively impaired (NCI) and early onset AD. We will examine exosomal properties related to Tau (Aim 1), p-Tau aggregation and seeding properties (Aim 2), and Tau pathology in the DMN connectome (Aim 3). Our group is uniquely qualified to explore these important translational questions due to the research experience and long-term collaboration of the team. We have involved ADRCs and DS research groups who are already funded to leverage resources in this timely and crucial area of biomedical research.